Acute myeloid leukemia (AML) is a morbid condition, with over 20,000 new cases and 10,000 deaths annually in the U.S. While the majority of patients achieve remission, most harbor minimal amounts of residual disease (MRD) that will ultimately lead to relapse. The ability to detect MRD is important as its presence is associated with increased risk of relapse and death, and there is considerable interest in modulating treatment intensity based on the presence or absence of MRD. Unfortunately, current MRD detection methods suffer from variable sensitivity, non-uniform performance across laboratories, and lack of broad applicability to all patients. There is an urgent, unmet need for a better MRD detection method, which could substantially benefit patients as well as other stakeholders. Next generation sequencing (NGS) permits detection of genetic aberrations on the subclonal level. As virtually all AML harbors mutations, NGS could be a platform for a ?universal? MRD assay. Unlike other detection methods, NGS would reveal specific mutations and could suggest targeted therapies. Enthusiasm for NGS for MRD detection has, until now, been tempered by the relatively poor sensitivity of this method. Duplex Sequencing, the most accurate NGS technology, can change the paradigm for MRD detection. Members of our team pioneered this proprietary technology and demonstrated in proof-of-principal studies that it can accurately detect leukemic clones at extremely low levels. In Phase I of this Fast Track application, we will refine steps in our sequencing procedures to facilitate industrial-scale deployment of our MRD assay and validate analytical performance. In Phase II, we assess our assay's performance based on banked AML samples. In Aim 1, we focus on whether our assay is prognostic of disease relapse. In Aim 2, we compare our assay to flow cytometry, the current gold standard for MRD detection. In Aim 3, we compare performance of our assay on paired bone marrow and peripheral blood samples to determine if we can achieve comparable results less invasively. The final product will be a robust, cost-effective, and implementable Laboratory Developed Test (LDT) ready for commercial deployment. This product will be widely useful for patients, oncologists, and payers alike by helping direct cutting-edge therapies to the patients most likely to benefit, while sparing others unnecessary medical and financial toxicities. It will allow researchers and pharmaceutical companies to rapidly evaluate novel therapies, permitting future clinical trials to be smaller and less costly. AML takes the lives of thousands of patients every year. Patients die both from the disease and from the aggressive treatment. Having an ultra-accurate ?universal? test to detect MRD would allow for improved prognostication and would pave the way for more efficacious personalized treatment. We fundamentally believe that such a test is necessary and well within our reach, and that our team is positioned better than any other in the world to bring this advance to patients.